Andrew P. Cope

Seropositive rheumatoid arthritis (RA) is an autoimmune disease whose course typically begins before joint involvement, during a period termed pre-RA, which is initially characterized by the presence of autoantibodies, including anti-citrullinated protein antibodies and rheumatoid factors. The ability to identify autoantibody-positive individuals who are at an increased risk of developing clinical RA has catalysed efforts to define the immune mechanisms underlying the initial break in self-tolerance and the subsequent transition to clinically apparent disease. Although not mutually exclusive, these investigations have broadly followed two complementary approaches: hypothesis-testing studies and agnostic multi-omics analysis. Hypothesis-testing studies have identified site-specific and isotype-specific patterns of mucosal anti-citrullinated protein antibodies and rheumatoid factor production, together with inflammation and/or dysbiosis associated with systemic autoimmunity, supporting a ‘mucosal origins hypothesis’. Cross-sectional and longitudinal multi-omics studies have demonstrated epitope spreading, pro-inflammatory biomarkers and dysregulated peripheral blood immune-cell populations with autoimmune characteristics. Epidemiological studies have further implicated certain environmental exposures in RA development. Collectively, these observations suggest that integrating molecular, cellular and environmental data through emerging data science and artificial intelligence approaches could help to identify pathogenic mechanisms underlying RA development and inform future prevention strategies.

Objective: In the first year after onset of the autoimmune disease RA (RA), 40-60% do not achieve remission on conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). To understand how autoreactive T cells may contribute to unstable or non-remission, we studied CD4+ T cells, including those recognising citrullinated (Cit) vimentin in participants with RA. Methods: Two cohorts of drug-naïve new-onset participants with RA were treated with csDMARDs. Disease activity score (DAS28-CRP) and peripheral blood (PB) mononuclear cells were collected longitudinally. In HLA-DR-shared epitope+ cohort 1 (n=21), T cells were assessed with a 17-marker spectral flow panel, incorporating HLA-DRB1*04:01/01:01- VimentinCit64 _59-71 or HLA-DRB1*04:04-VimentinCit71 _66-78 tetramers. Changes in T cell subsets over time were assessed in remitting and non-remitting participants using a generalized linear mixed model with a negative binomial distribution. In cohort 2 (n=26), the transcriptome of disaggregated synovial tissue (ST) and PB CD4+ T cells were analysed at baseline, and ST biopsy spatial proteomics at baseline and 6 months. Results: CD4⁺CXCR5 ^- PD1 ⁺ peripheral helper T cells (Tph), including Cit-vimentin-reactive Tph, CD4⁺CCR7 ⁺ CXCR5 ^- PD1 ⁺ stem-like Tph and TIGIT+PD1+ Tph were increased with moderate/high DAS28-CRP at any time point. Remission outcome was associated with low CD4⁺ follicular helper T cell (Tfh) and Cit-vimentin-reactive Tfh. In non-remitting participants, Tph/fh infiltrated germinal-centre-like ST aggregates. This decreased in remission. Circulating TIGIT ⁺ Tph genes reflected B lymphoid activation and lymph node egress, while in ST they reflected local differentiation. Conclusion: Persistently high circulating TIGIT ⁺ Tph and Tfh, including Cit-vimentin specificities, reflecting antigen-presenting B-cell interactions, are associated with reduced response to csDMARDs in recent-onset RA. Key messages: What is already known on this topic: Tph and Tfh cells interacting with B cells are implicated in active ACPA+ RA Citrullinated (Cit)-vimentin is an important neutrophil extracellular trap-derived target of ACPA What this study adds: High circulating TIGIT+ Tph, Cit-vimentin-autoreactive Tph and Tfh associate with failure to reach remission on conventional synthetic DMARDs within the first year in early HLA-DR shared-epitope+ RA Tph/Tfh and adjacent regulatory T cells surround follicular B-cells in lymphoid aggregates in synovial tissue in non-remission Circulating TIGIT+ Tph bear a transcriptional signature of lymphoid tissue expansion and lymph node egress as compared to functional differentiation and antigen experience in synovial tissue How this study might affect research, practice or policy: When a remission target is not achieved in HLA-DR shared-epitope+ RA patients during the first year of treatment, high circulating TIGIT+ Tph implicate autoreactive T-B-lymphoid expansion in synovial tissue.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key negative regulator of T cell activation, acting with C-terminal Src kinase (Csk) to suppress early T cell receptor (TCR) signaling and maintain immune tolerance. Given that the autoimmune disease–associated R620W variant alters T cell responses, we investigated the effects of PTPN22 on T cell activation. We identified a role for PTPN22 in modulating cytoskeletal dynamics at the immunological synapse in Jurkat cells through its interaction with proline-serine-threonine phosphatase–interacting protein 1 (PSTPIP1), a cytoskeletal adaptor protein that recruits actin nucleation–promoting factors, including WASp, to the TCR. PTPN22 deficiency or inhibition disrupted Arp2/3-dependent actin remodeling, leading to excessive central F-actin foci, PSTPIP1 mislocalization, and enhanced Ca ²⁺ signaling, especially under low-affinity stimulation of the TCR. Super-resolution DNA-PAINT analysis revealed that loss of PTPN22 promoted aberrant PSTPIP1-TCR nanoscale colocalization and increased TCR clustering. These findings uncover a PTPN22-PSTPIP1 signaling axis that is critical for regulating cytoskeletal remodeling and receptor organization, providing insights into T cell hyperactivation that may be relevant to autoimmune disease.

Objectives: To evaluate temporal changes in the incidence and prevalence of 19 long-term conditions in England, quantifying the impact of the COVID-19 pandemic on diagnosis rates by disease, age group, sex, socioeconomic status, and ethnicity. Design: Observational cohort study. Setting: Primary care and hospital admission data, with the approval of NHS England. Participants: 27,132,190 individuals registered with general practices in England contributing data to the OpenSAFELY-TPP platform. Main outcomes measures: Temporal trends in age and sex-standardised incidence and prevalence were evaluated for 19 long-term conditions between April 1, 2016, and November 30, 2024. Differences between expected and observed incidence rates after the onset of the COVID-19 pandemic were compared using seasonal autoregressive integrated moving-average models. Results: Between March 2020 and November 2024, persistent large deficits in incident diagnoses were evident for depression (738,068 [28.0%] fewer diagnoses than expected; 95% CI 701,452 to 774,685), asthma (150,708 [16.0%] fewer diagnoses; 95% CI 133,300 to 168,117), COPD (84,084 [15.1%] fewer diagnoses; 95% CI 74,342 to 93,827), osteoporosis (78,891 [16.5%] fewer diagnoses; 95% CI 72,804 to 84,978) and psoriasis (56,231 [17.6%] fewer diagnoses; 95% CI 51,054 to 61,407). Conversely, post-pandemic diagnoses of chronic kidney disease (CKD) have increased by 32.7% above expected levels, corresponding to 325,996 additional diagnoses (95% CI 252,212 to 399,779). Dementia diagnoses have rebounded above pre-pandemic levels for individuals of White ethnicity and less deprived socioeconomic quintiles, but remain lower than expected for individuals from other ethnicities and more deprived communities. Conclusions: There has been a lasting and disproportionate impact of the pandemic on conditions including depression, asthma, COPD and osteoporosis, contrasting a post-pandemic surge in CKD diagnoses. Analyses stratified by ethnicity and socioeconomic status reveal inequity in the recovery from the pandemic, particularly for individuals with dementia. Importantly, this study demonstrates the potential for near real-time monitoring of disease epidemiology using routinely collected health data, informing strategies to enhance case detection and address healthcare disparities. Summary box: What is already known: Early in the COVID-19 pandemic, large deficits in newly-recorded diagnoses were reported for a range of long-term conditions, including chronic obstructive pulmonary disease (COPD), depression, asthma and rheumatoid arthritis. However, no population-level studies have evaluated whether diagnosis rates have subsequently recovered as healthcare services emerge from the pandemic, or compared the impact by disease, age group, sex, socioeconomic status, and ethnicity. What this study adds: Large deficits in diagnoses remain evident for conditions including depression, COPD, asthma, osteoporosis and psoriasis, contrasting a surge in new diagnoses of chronic kidney disease since 2022. Diagnosis rates for dementia have reached pre-pandemic levels for individuals of White ethnicity and those from less deprived socioeconomic communities, but remain lower than expected among individuals from other ethnicities and more deprived communities. This study demonstrates how routinely collected health data can transform monitoring of disease epidemiology in near real-time and highlight healthcare inequity.

Mental health has been shown to impact rheumatoid arthritis (RA) outcomes and is associated with self-management behaviors. The extent to which mental health impacts outcomes via different self-management behaviours has not been thoroughly investigated. Adult RA patients who were starting a new medication or dosage were recruited to a prospective cohort with follow-ups at 3 and 12-months covering clinical and patient-reported outcomes. The longitudinal relationships between mental health, self-management behaviors (diet, physical activity, sleep, smoking, alcohol, and medication nonadherence), disease outcome, and function were assessed. Self-management behaviors were considered mediators of mental health at baseline on outcomes at 3 and 12 months. Depression did not worsen the odds of EULAR response for the total PHQ at 3 months (OR = 0.96, p = 0.36) or 12 months (OR = 0.99, p = 0.99) nor for the categorical PHQ at 3 months (OR = 0.64, p = 0.34) or 12 months (OR = 0.67, p = 0.44). Anxiety also did not worsen the odds of EULAR response for the total GAD at 3 months (OR = 0.98, p = 0.76) or 12 months (OR1.04, 0.53) nor for the categorical GAD at 3 months (OR = 0.99, p = 0.99) or 12 months (OR = 0.94, p = 0.75). However, depression was associated with the DAS-28 at 3 months (b = 0.22, p = 0.04). Among the self-management behaviors, insomnia was found to be a significant mediator between depression and the WSAS (b = 0.08, p = 0.03) as well as anxiety and the WSAS (b = 0.07, p = 0.03). Alcohol was also a significant mediator between depression and the DAS-28 (b = 0.21, p = 0.04). Mental health was associated with worse quality of life and disease outcomes, but not EULAR response. Self-management behaviors were associated with disease outcomes and mental health.